Interstitial Lung Disease Julye N. Carew, M.D. January 12, 2007

Interstitial Lung Diseases Definition Clinical Presentation and evaluation Radiographic Features Classification Treatment Prognosis

Definition “Interstitial lung disease”- a misnomer Few cells in the interstitium of the normal lung Injury to basement membrane shared by epithelium and endothelium Increased alveolar permeability and spillage of serum contents into the alveolar space and recruitment of fibroblasts Collagen deposition Also injury to small airways=respiratory bronchioles, alveolar ducts and terminal bronchioles

Alveolar/Interstitial Space Matrix Connective tissue Murray and Nadel, Text of Resp. Medicine

Pathogenesis Epithelial cell apoptosis with loss of basement membrane integrity: production of growth factors in response to alveolar epithelial injury with hyperplastic type II cells and myofibroblast recruitment Noble, et al. Clinics in Chest Med, Dec 2004

Pathogenesis UNKNOWN!!! Some understanding of the mechanism of injury Initiating injuries are likely multiple= inhaled, sensitization to allergens, circulatory With continued injury, “repair” process continues with additional fibroproliferation that is unchecked

ILD 81 in 100,000 prevalence in men 67 in 100,000 in women 32.5 in 100,000 incidence in men 26 in 100,000 in women 200 in 100,000 incidence in age >75 30-40% of all ILD “IPF”

ILD Due to increasing numbers of cytotoxic drugs, increased detection of occupational lung disease and increasing life expectancy, as well as better imaging and diagnostic testing the incidence of these diseases is expected to rise

Evaluation of ILD EXTENSIVE HISTORY AGE, GENDER, UNDERLYING COMORBIDITIES, DRUGS, SMOKING, OCCUPATIONAL HISTORY, HOBBIES, PETS, FAMHX DURATION OF SYMPTOMS PHYSICAL EXAM LABORATORIES IMAGING SPIROMETRY, LUNG VOLUMES AND DLCO

Laboratories LFTs, CBC ANA, RF, hypersensitivity panels, ANCA, anti-GBM ?CRP, ESR

Pulmonary function Spirometry Lung volumes Diffusion capacity

Spirometry UpToDate, 2007

Lung Volumes UpToDate, 2007

Diffusion capacity UpToDate, 2007

Diffusion Matrix Connective tissue Murray and Nadel, Text of Resp. Medicine

Imaging PA/LAT CXR HRCT

GROUND GLASS Schwarz, ILD, 2003, RB

NODULAR GROUND GLASS Schwarz, ILD, 2003, HP

INTRALOBULAR SEPTAL THICKENING Schwarz, ILD, 2003, LC

RETICULAR INFILTRATES Schwarz, ILD, 2003, HP

HONEYCOMB LUNG Schwarz, ILD, 2003

HONEYCOMB LUNG

Clinical Classification Connective Tissue Diseases Drug-induced Primary Unclassified Occupational Idiopathic Disorders

Clinical Classification-- CTD Scleroderma Polymyositis-dermatomyositis Systemic lupus erythematosus Rheumatoid arthritis** Mixed connective tissue disease Ankylosing spondylitis Behcet’s Sjogren’s syndrome

RA

Rheumatoid Arthritis Interstitial fibrosis Male predominance 3:1 High titers of RF and rheumatoid nodules Occurs in 33% of all RA patients Usually patients are dyspneic, but also limited by joint disease Therapies may cause fibrosis (gold, methotrexate, penicillamine)

RA Schwarz and King, ILD 2003

Drugs Antibiotics--nitrofurantoin, sulfasalazine, ethambutol Antiarrhythmics--amiodarone, tocainide, propranolol Anti-inflammatories--gold, penicillamine Anticonvulsants--dilantin Chemotherapeutic agents--mitomycin C, bleomycin, busulfan, cyclophosphamide, chlorambucil, methotrexate, azathioprine, BCNU [carmustine], procarbazine Therapeutic radiation Oxygen toxicity Narcotics Cocaine Paraquat

Primary- Unclassified Sarcoidosis Eosinophilic granuloma Amyloidosis Lipoid pneumonia Lymphangitic carcinomatosis Broncholaveolar carcinoma Pulmonary lymphoma Gaucher's disease Niemann-Pick disease Hermansky-Pudlak syndrome Neurofibromatosis LAM Tuberous sclerosis Acute respiratory distress syndrome AIDS Bone marrow transplantation Postinfectious Eosinophilic pneumonia Alveolar proteinosis Diffuse alveolar hemorrhage syndromes Alveolar microlithiasis Metastatic calcification

Occupational Silicosis- tile, glass Asbestosis Hard-metal pneumoconiosis   Coal worker's pneumoconiosis   Berylliosis-fluorescent bulbs, dental, electronics  Aluminum oxide fibrosis-abrasives  Talc pneumoconiosis   Siderosis (arc welder)-iron foundry, welders Stannosis (tin)

Idiopathic Acute interstitial pneumonitis (Hamman-Rich syndrome) Idiopathic pulmonary fibrosis “IPF” Familial idiopathic pulmonary fibrosis Desquamative interstitial pneumonitis Respiratory bronchiolitis Cryptogenic organizing pneumonia Nonspecific interstitial pneumonitis Lymphocytic interstitial pneumonia (Sjögren's syndrome, connective tissue disease, AIDS, Hashimoto's thyroiditis) Autoimmune pulmonary fibrosis (inflammatory bowel disease, primary biliary cirrhosis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia)

Idiopathic ILD Diagnosis is made based upon clinical history, radiographic findings and pathology Some pathologic findings are pathognomonic for a particular disease, while others are suggestive in the correct clinical setting

IPF Major Criteria Minor Criteria • Exclusion of other known causes of ILD, such as certain drug toxicities, environmental exposures, and connective tissue diseases • Abnormal pulmonary function studies that include evidence of restriction (reduced VC often with an increased FEV1 /FVC ratio) and impaired gas exchange [increased AaPo2 with rest or exercise or decreased DLCO ] • Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT scans • Transbronchial lung biopsy or bronchoalveolar lavage (BAL) showing no features to support an alternative diagnosis Minor Criteria • Age > 50 yr • Insidious onset of otherwise unexplained dyspnea on exertion • Duration of illness 3 mo • Bibasilar, inspiratory crackles (dry or “Velcro” type in quality) IPF consensus statement, 2000, AJRCCM

Idiopathic pulmonary fibrosis Pathology=UIP Schwarz, ILD, 2003

Treatment Very limited literature, NO RANDOMIZED TRIALS ATS recommendations: Prednisone 60 mg daily tapering or 20 mg plus Cytoxan 100-120 mg/day Retrospective case review (n=78 with OLB), UIP=38, NSIP=28, RB/DIP=13 At 6 months, 11% UIP, 29% NSIP, 80% RB/DIP improved Nicholson, AJRCCM, 2000

Treatment of IPF Azathioprine

Treatment of IPF Colchicine 1998 and 2000 studies (Douglas et al., AJRCCM) compared colchicine to prednisone and other combinations and showed no difference in survival in any of the groups but with fewer side effects with Colchicine NAC

Treatment of IPF Gamma interferon Th-1 cytokine that induces CD4 cells to the Th1 phenotype, inhibits the proliferation of fibroblasts and downregulates TGF-β Administered subcu three times weekly Flu-like symptoms Mixed results with this drug in trials, but may be due to the fact that it needs to be used earlier in disease

Treatment of IPF Pirfenidone Pyridone molecule that inhibits TGF-β-stimulated collagen production Ameliorates bleomycin-induced fibrosis in hamsters Undergoing stage III trials

IPF King, et al., AJRCCM, 2001

DIP Clinical classification=pathology DISEASE OF SMOKERS!! 4th-5th decades Subacute cough and dyspnea CT shows diffuse GG infiltrates Smoking cessation

DIP Schwarz, ILD, 2003

DIP Leslie, Clinics in Chest Med, 2006

RB-ILD SMOKING DISEASE!! Similar to DIP, but pathology slightly different, in peribronchiolar distribution Smoking cessation +/- steroids

RB-ILD Schwarz, ILD, 2003

LIP Characterized by monotonous sheets of polyclonal lymphocytes Clinical=pathology Uncommon Associated with Sjogren’s and AIDS May remit with steroids and other ISD, progress to fibrosis, lead to infectious complications, or develop lymphoma

LIP Leslie, Clinics in Chest Med, 2006

NSIP Originally represented “difficult to characterize” Clearly represents a separate disease from IPF Primary and secondary forms (HP, drugs, CVD, AIDS and transplants) Second most common diagnosis Middle-aged, majority smoker’s Surgical biopsy required to make diagnosis HOMOGENEOUS ?? Early UIP

NSIP Leslie, Chest, 128:5, 2005

Interstitial pneumonias American Thoracic Society/European Respiratory Society classification of the idiopathic interstitial pneumonias Histologic pattern Clinico-radiologic-pathologic UIP IPF NSIP NSIP Organizing pneumonia COP Diffuse alveolar damage (DAD) AIP Respiratory bronchiolitis pattern RBILD Desquamative pattern DIP Lymphoid pattern LIP